U.S. patent application number 12/630298 was filed with the patent office on 2010-06-10 for apparatus and method for automated quality control.
This patent application is currently assigned to Siemens Medical Solutions USA, Inc.. Invention is credited to Carroll Edward Ball, Arkadij M. Elizarov, Hartmuth C. Kolb, Reza Miraghaie, Jianzhong Zhang.
Application Number | 20100145630 12/630298 |
Document ID | / |
Family ID | 42232034 |
Filed Date | 2010-06-10 |
United States Patent
Application |
20100145630 |
Kind Code |
A1 |
Ball; Carroll Edward ; et
al. |
June 10, 2010 |
Apparatus and Method for Automated Quality Control
Abstract
Methods and apparatus to assess current aspects of Quality
Control useful for release of radioactive compounds for imaging,
such as PET tracers as injectables, in an automated manner, without
user interference, and in compliance with regulatory guidelines.
The present method and system relates to an integrated automated
quality control analysis of a substance utilizing a single sample
injection for a plurality of inline quality control tests. A
quantitative analysis of the sample via the plurality of quality
control tests is conducted. A measurement value of each of the
plurality of quality control parameters is determined and a
comparison of each measurement value of the plurality of quality
control parameters with a predetermined corresponding criterion
value is made. A cumulative quality rating for the sample is
determined and the validated sample is released based on the
quality rating.
Inventors: |
Ball; Carroll Edward; (Los
Angeles, CA) ; Elizarov; Arkadij M.; (Woodland Hills,
CA) ; Kolb; Hartmuth C.; (Playa Del Rey, CA) ;
Miraghaie; Reza; (Culver City, CA) ; Zhang;
Jianzhong; (Brea, CA) |
Correspondence
Address: |
SIEMENS CORPORATION;INTELLECTUAL PROPERTY DEPARTMENT
170 WOOD AVENUE SOUTH
ISELIN
NJ
08830
US
|
Assignee: |
Siemens Medical Solutions USA,
Inc.
Mavern
PA
|
Family ID: |
42232034 |
Appl. No.: |
12/630298 |
Filed: |
December 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61119899 |
Dec 4, 2008 |
|
|
|
Current U.S.
Class: |
702/31 |
Current CPC
Class: |
G01N 2033/0093 20130101;
G01N 15/06 20130101; G01N 2030/8804 20130101; G01N 35/00663
20130101 |
Class at
Publication: |
702/31 |
International
Class: |
G06F 19/00 20060101
G06F019/00 |
Claims
1. A method for an integrated automated quality control analysis of
a compound comprising the following steps: utilizing a single
sample injection for a plurality of inline quality control tests;
conducting a quantitative analysis of the sample via the plurality
of quality control tests; determining a measurement value of each
of the plurality of quality control parameters; comparing each
measurement value of the plurality of quality control parameters
with a predetermined corresponding criterion value; determining a
cumulative quality rating for the sample; and releasing a report
validating the sample based on the said quality rating, wherein the
single sample injection is used for every control test required for
the sample.
2. The method according to claim 1, wherein a plurality of quality
control tests comprises determination of particle and color
content.
3. The method according to claim 2, wherein a single optical cell
is used for the determination of color.
4. The method according to claim 2, wherein a single optical cell
is used for the determination of a color parameter and appearance
parameter.
5. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of sterility via a
filter membrane integrity test.
6. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of radionuclidic
purity.
7. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of radioactive
concentration.
8. The method according to claim 7, wherein the determination of
radioactive concentration includes variable detection
sensitivity.
9. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of pH of the sample
solution.
10. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of Kryptofix
concentration.
11. The method according to claim 10, wherein the determination of
Kryptofix concentration includes a microfluidic test.
12. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of radiochemical
identity.
13. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of radiochemical
purity.
14. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of specific activity
of the sample.
15. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of bacterial
endotoxin concentration.
16. The method according to claim 1, wherein a plurality of quality
control tests further comprises determination of residual solvent
content.
17. The method according to claim 1, further comprising a G.C. test
for determination of residual solvent content and Kryptofix.
18. The method according to claim 1, further comprising determining
K222 concentration and solvent concentration from a single GC
injection.
19. The method according to claim 1, further comprising determining
K222 concentration by GC.
20. The method according to claim 1, further comprising determining
specific activity from a single HPLC injection.
21. The method according to claim 1, further comprising performing
a microfluidic K222 test.
22. The method according to claim 1, wherein two or more tests are
inline.
23. The method according to claim 1, wherein two or more tests
performed in parallel.
24. The method according to claim 1, wherein the compound is a
radiopharmaceutical.
25. The method according to claim 1, wherein the compound is a PET
tracer.
26. A method for an automated quality control analysis of a PET
tracer comprising determining a measurement value for each of the
following quality control parameters: particle and color content;
filter membrane integrity; radionuclidic purity; radioactive
concentration; pH of the sample solution; Kryptofix concentration;
radiochemical identity; radiochemical purity; specific activity of
the sample; bacterial endotoxin concentration; residual solvent
concentration; comparing each measurement value of the quality
control parameters with a predetermined corresponding criterion
value; determining a cumulative quality rating for the
radiopharmaceutical agent; and releasing a report validating the
sample based on the said quality rating.
27. The method according to claim 26, wherein two or more tests are
inline
28. The method according to claim 26, wherein two or more tests are
run in parallel.
29. An apparatus for automated quality control analysis of a PET
tracer comprising the following elements: an injection valve
configured to deliver the sample from a vial via a syringe in to
the sample line; at least one sample line filled with the sample
for a plurality of quality control tests; a distribution valve; a
filter membrane integrity test setup; an optical cell for color
and/or appearance test connected to a light source and/or a laser
and a spectrometer via fiber optics; a HPLC column; a UV cell
connected to a UV light source and a UV detector via fiber optics;
a radioactivity detection modules; a GC column; a pH test cell, one
or more ports to operatively couple the elements to a computer
system for quantitative processing of the experimental data and
generation of a report reflecting the quality of the sample against
the predetermined standards.
30. The apparatus according to claim 29, wherein two or more
elements are inline.
31. The apparatus according to claim 29, wherein two or more tests
are run in parallel.
32. The apparatus according to claim 29, wherein two or more tests
are run sequentially.
33. The apparatus of claim 29, capable of performing an automated
self-cleaning and recalibration cycle.
34. The apparatus of claim 29 wherein the apparatus is
portable.
35. The apparatus of claim 29 further comprising radiation
shielding disposed proximal to one or more of the elements.
36. The apparatus of claim 29, wherein the computer system is
located remotely from the apparatus.
37. A quality control system comprising: an apparatus for automated
quality control analysis of a sample; and a synthesis module for
originating the sample, wherein the apparatus comprises the
following elements: an introduction module configured to deliver
the sample from a vial; at least one sample line filled with the
sample for a plurality of quality control tests; a distribution
valve; a filter membrane integrity test setup; an optical cell for
color and/or appearance test connected to a light source and/or a
laser and a spectrometer via fiber optics; a HPLC column; a UV cell
connected to a UV light source and a UV detector via fiber optics;
a radioactivity detection module; a GC column; a pH test cell; one
or more ports to operatively couple the elements to a computer
system for quantitative processing of the experimental data and
generation of a report reflecting the quality of the sample against
the predetermined standards.
38. The system as claimed in claim 37, wherein the vial includes
radiation shielding.
39. The system as claimed in claim 37 wherein the apparatus is
operatively coupled to the synthesis module.
40. The system as claimed in claim 37 wherein the apparatus is
fluidically coupled to the synthesis module.
41. The system as claimed in claim 37 wherein the apparatus is
mechanically coupled to the synthesis module.
42. The system as claimed in claim 37 wherein the apparatus is
electronically coupled to the synthesis module.
Description
CLAIM TO PRIORITY
[0001] The present application is based on and claims priority to
U.S. provisional application No. 61/119,899, filed Dec. 4, 2008,
which is hereby incorporated by reference in its entirety
herein.
[0002] The foregoing application, and all documents cited therein
or during their prosecution ("appln cited documents") and all
documents cited or referenced in the appln cited documents, and all
documents cited or referenced herein ("herein cited documents"),
and all documents cited or referenced in herein cited documents,
together with any manufacturer's instructions, descriptions,
product specifications, and product sheets for any products
mentioned herein or in any document incorporated by reference
herein, are hereby incorporated herein by reference, and may be
employed in the practice of the invention.
FIELD OF THE INVENTION
[0003] The present invention relates generally to a system and
method for automated quality control analysis of a compound. More
specifically, the present invention relates to systems and methods
for automated quality control analysis of a compound that utilizes
a single sample injection for a plurality of inline quality control
tests where some of the test stations are in line while others
receive their sample via robotics and some do not require a
sample.
BACKGROUND DISCUSSION
[0004] Quality Control (QC) devices and methods have become an
increasingly important part of healthcare over the last few
decades. Specifically in healthcare, QC has traditionally occurred
at the site of the manufacturer, as opposed to the point of use.
However, with the development of new contrast agents and other
short half-life pharmaceutical products, it may be necessary to
perform compounding or processing steps immediately prior to
administration into a patient. Prior to injection, the safety and
efficacy of the substance should be ensured. As such, Quality
Control is important for radio-synthesized Positron Emission
Tomography (PET) tracers that are to be used in clinical and
research circumstances. The QC of radiotracers generally involves
manual execution and subjective analysis in tests such as color and
appearance, pH, radioactivity concentration, radiochemical purity,
etc.
[0005] The quality requirements for radiotracers are set out in
various pharmacopoeia including United States Pharmacopeia (USP),
British Pharmacopeia (BP), European Pharmacopeia (EP), etc. It
should be noted that the quality control requirements of various
radiotracers differ among different countries as different
countries may adopt a different set of standards.
SUMMARY OF THE INVENTION
[0006] One embodiment of the present invention is directed to an
apparatus and method for automated quality control. The method is
for an integrated automated quality control analysis of a compound
that includes utilizing a single sample injection for a plurality
of inline quality control tests. A quantitative analysis of the
sample via the plurality of quality control tests is conducted and
a measurement value of each of the plurality of quality control
parameters is determined. Each measurement value of the quality
control parameters is compared with a predetermined corresponding
criterion value and a cumulative quality rating for the sample is
determined. The validated sample is released based on the quality
rating.
[0007] Another embodiment of the present invention is directed to
the method described above and further includes a control parameter
of particle and color content.
[0008] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of filter membrane integrity.
[0009] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of radionuclidic purity.
[0010] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of radioactive concentration.
[0011] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of pH of the sample solution.
[0012] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of Kryptofix concentration.
[0013] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of radiochemical identity.
[0014] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of radiochemical purity.
[0015] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of specific activity of the sample.
[0016] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of bacterial endotoxin concentration.
[0017] Yet another embodiment of the present invention is directed
to the method described above and further includes a control
parameter of residual solvent concentration.
[0018] Yet another embodiment of the present invention is directed
to the method described above and further includes determining a
cumulative quality rating for the compound.
[0019] Yet another embodiment of the present invention is directed
to the method described above and further includes releasing a
validated dose of the sample based on the quality rating.
[0020] Yet another embodiment of the present invention is directed
to the method described above and the compound includes a
radiopharmaceutical, which may include a PET tracer.
[0021] Yet another embodiment of the present invention is directed
to the method described above and further includes determining K222
concentration and solvent concentration from a single GC
injection.
[0022] Yet another embodiment of the present invention is directed
to the method described above and further includes determining K222
concentration by GC.
[0023] Yet another embodiment of the present invention is directed
to the method described above and further includes determining
specific activity from a single HPLC injection.
[0024] Yet another embodiment of the present invention is directed
to the method described above and further includes performing a
microfluidic K222 test.
[0025] Yet another embodiment of the present invention is directed
to an apparatus, or a system, for an automated quality control
analysis of a PET tracer sample. The apparatus includes an
injection valve to deliver the sample from a vial via a syringe in
to the sample line. There is at least one sample line filled with
the sample for a plurality of quality control tests. The apparatus
also includes a distribution valve and station for testing the
integrity of a filter membrane. Furthermore, an optical cell that
is used for color and/or appearance testing is connected to a light
source and/or a laser and a spectrometer via fiber optics. The
apparatus also includes an HPLC pump, a HPLC column, a UV cell
connected to a UV light source and a UV detector via fiber optics.
The apparatus also includes radioactivity detection modules, a GC
column, and a pH test cell with a pH electrode. The tests are
performed using the various modules and a processor is used for
quantitative processing of the experimental data and generation of
a report reflecting the quality of the sample against predetermined
standards.
[0026] Yet another embodiment of the present invention is directed
to the apparatus described above and the apparatus is portable.
[0027] Yet another embodiment of the present invention is directed
to the apparatus described above and further including radiation
shielding disposed proximal to one or more of the elements.
[0028] Yet another embodiment of the present invention is directed
to the apparatus described above in which the computer system is
located remotely from the apparatus.
[0029] Yet another embodiment of the invention is directed to a
quality control system that includes an apparatus for automated
quality control analysis of a sample; and a synthesis module for
originating the sample. The apparatus comprises the following
elements: [0030] an introduction module configured to deliver the
sample from a vial; [0031] at least one sample line filled with the
sample for a plurality of quality control tests; [0032] a
distribution valve; [0033] a filter membrane integrity test setup;
[0034] an optical cell for color and for appearance test connected
to a light source and/or a laser and a spectrometer via fiber
optics; [0035] a HPLC column; [0036] a UV cell connected to a UV
light source and a UV detector via fiber optics; [0037] a
radioactivity detection module; [0038] a GC column; [0039] a pH
test cell; [0040] one or more ports to operatively couple the
elements to a computer system for quantitative processing of the
experimental data and generation of a report reflecting the quality
of the sample against the predetermined standards. Yet another
embodiment of the present invention is direct to the system as
described above wherein the vial includes radiation shielding.
[0041] Yet another embodiment of the present invention is direct to
the system as described above wherein the apparatus is operatively
coupled to the synthesis module.
[0042] Yet another embodiment of the present invention is direct to
the system as described above wherein the apparatus is fluidically
coupled to the synthesis module.
[0043] Yet another embodiment of the present invention is direct to
the system as described above wherein the apparatus is mechanically
coupled to the synthesis module.
[0044] Yet another embodiment of the present invention is direct to
the system as described above wherein the apparatus is
electronically coupled to the synthesis module.
[0045] Additionally other embodiments of the present invention
include:
[0046] 1. Inline structure: one injection fills the majority of the
test modules.
[0047] 2. Variable radioactivity detection sensitivity: greatly
reduces the analysis time.
[0048] 3. GC test for both organic solvents and Kryptofix.
[0049] 4. One optical cell for both color and appearance (clarity)
tests.
[0050] 5. Pressure drop for filter membrane test.
[0051] 6. Microfluidics Kryptofix test.
[0052] These and other various embodiments of the present
invention, together with the organization and manner of operation
thereof, will become apparent from the following detailed
description when taken in conjunction with the accompanying
drawings. The entire disclosures of all patents and references
cited throughout this application are incorporated herein by
reference in their entirety.
[0053] It is noted that in this disclosure and particularly in the
claims and/or paragraphs, terms such as "comprises", "comprised",
"comprising" and the like can have the meaning attributed to it in
U.S. patent law; e.g., they can mean "includes", "included",
"including", and the like; and that terms such as "consisting
essentially of" and "consists essentially of" have the meaning
ascribed to them in U.S. patent law, e.g., they allow for elements
not explicitly recited, but exclude elements that are found in the
prior art or that affect a basic or novel characteristic of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0054] Embodiments of the invention are described by referring to
the attached drawings, in which:
[0055] FIG. 1 illustrates a flowchart of steps according to an
embodiment of the present invention;
[0056] FIGS. 2A and 2B illustrate embodiments of apparatuses in
accordance with the present invention;
[0057] FIG. 3 shows a schematic for a filter membrane integrity
test;
[0058] FIG. 4 shows a schematic for an automated radiochemical QC
system;
[0059] FIG. 5 shows a schematic including GC unit, HPLC unit,
radionuclidic purity unit, color and appearance (clarity) unit and
pH unit;
[0060] FIG. 6 shows membrane integrity test results in accordance
with an embodiment of the present invention;
[0061] FIG. 7 shows UV absorbance and radioactivity chromagrams
generated through HPLC separation an detection of [.sup.18F]FLT in
accordance with an embodiment of the present invention;
[0062] FIG. 8 shows radionuclidic test results based of decay
measurement of [.sup.18F]FLT in accordance with an embodiment of
the present invention;
[0063] FIG. 9 shows ethanol, acetonitrile and Kryptofix test
results in accordance with an embodiment of the present
invention;
[0064] FIG. 10 shows a microfluidic structure used to characterize
Kryptofix content in a sample in accordance with an embodiment of
the present invention;
[0065] FIG. 11 illustrates a device to block venting holes of a
filter in accordance with an embodiment of the present
invention;
[0066] FIG. 12 shows a schematic for test parameters according to
an embodiment of the present invention; and
[0067] FIG. 13 shows a schematic for color and appearance test
according to an embodiment of the present invention;
[0068] FIG. 14 shows an example of a QC system for a plurality of
tests according to the present invention;
[0069] FIG. 15 shows a schematic for color and appearance test and
a filter membrane integrity test;
[0070] FIG. 16 shows a schematic for an automated radiochemical QC
system radionuclidic purity test, radioactivity concentration test,
pH test and Kryptofix test; and
[0071] FIG. 17 shows a perspective view of an automated QC
apparatus.
DETAILED DESCRIPTION
[0072] In the following description, for purposes of explanation
and not limitation, details and descriptions are set forth in order
to provide a thorough understanding of the present invention.
However, it will be apparent to those skilled in the art that the
present invention may be practiced in other embodiments that depart
from these details and descriptions.
[0073] As used in this application, the terms "component" and
"system" are intended to refer to a computer-related entity, either
hardware, a combination of hardware and software, software, or
software in execution. For example, a component may be, but is not
limited to being, a process running on a processor, a processor, an
object, an executable, a thread of execution, a program, and/or a
computer. By way of illustration, both an application running on a
server and the server can be a component. One or more components
may reside within a process and/or thread of execution and a
component may be localized on one computer and/or distributed
between two or more computers.
[0074] There are disclosed, as various embodiments of the present
invention, methods and apparatus for performing an automated
quality control test for a plurality of control parameters. For
example, embodiments of the present invention include a plurality
of tests.
[0075] Typical manual QC (quality control) operation for PET
tracers is labor intensive and time consuming. Some results of
manual tests rely on the interpretation of experienced operators.
The manual operation presents hazardous exposure to the operators.
Also many aspects of manual QC rely on non-quantitative data and
the pharmacist's opinion.
[0076] An automated QC system according to embodiments of the
present invention may be used, for example, for radio-synthesized
tracers, covering a plurality of tests, which assess, for example:
1. particle and color content; 2. sterility based on filter
membrane integrity; 3. radionuclidic purity; 4. radioactive
concentration; 5. pH of a sample solution; 6. Kryptofix
concentration; 7. radiochemical identity; 8. radiochemical purity;
9. specific activity of the sample; 10. bacterial endotoxins
concentration; and 11. residual solvent volume.
[0077] The embodiments of the present invention enable simplified
and automated operation. The test results are quantitative, the
testing modules are inline, and the tests may be performed in
parallel. As a result, the test results are more reliable, the
operator is less susceptible to radiation, and the whole process is
more economical and efficient as time and labor for the QC are
significantly reduced.
[0078] Furthermore, as stated herein, embodiments of the present
invention provide a single injection sample test procedure for
multiple parameters to determine acceptability of the sample. Each
specific test has associated predetermined criteria that the sample
must pass. The time for performing all the inline tests is
approximately 15 minutes; but a single operator, or technician may
supervise the testing since parameter takes less than a minute to
perform, using the automated inline methods and apparatus described
herein.
[0079] In the following description, for purposes of explanation
and not limitation, details and descriptions are set forth in order
to provide a thorough understanding of the present invention.
However, it will be apparent to those skilled in the art that the
present invention may be practiced in other embodiments that depart
from these details and descriptions.
Some Definitions:
[0080] A "radiolabeled compound" is a compound where one or more of
the atoms of the molecule is substituted for a radioactive isotope,
such as in radioactive tracing. Radiolabeled compounds are
compounds that can bind target sites in the body, including, but
not limited to, for example, the brain.
[0081] The term "radioactive isotope" refers to isotopes exhibiting
radioactive decay (e.g., emitting positrons). Such isotopes are
also referred to in the art as radioisotopes or radionuclides.
Radioactive isotopes or the corresponding ions, such as the
fluoride ion, are named herein using various commonly used
combinations of the name or symbol of the element and its mass
number and are used interchangeably (e.g., 18F, [18F], F-18,
[F-18], fluorine-18). Exemplary radioactive isotopes include 124I,
18F, 11C, 13N and 15O, which have half-lives of 4.2 days, 110
minutes, 20 minutes, 10 minutes, and 2 minutes, respectively.
[0082] Positron Emission Tomography (PET) is a molecular imaging
technology that is increasingly used for detection of disease. PET
imaging systems create images based on the distribution of
positron-emitting isotopes in the tissue of a patient. The isotopes
are typically administered to a patient by injection of probe
molecules, which comprise a positron-emitting isotope, e.g.
carbon-11, nitrogen-13, oxygen-15, or fluorine-18, attached to a
molecule that is readily metabolized or localized in the body or
that chemically binds to receptor sites within the body. The short
half-lives of the positron emitters require that synthesis,
purification and analysis, such as QC of the probes are completed
rapidly. Such compounds include, but are not limited to 18F-FLT
([18F]fluorothymidine), 18F-FDDNP
(2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]2-naphthyl}ethylidene)maloni-
trile), 18F-FHBG (9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine
or [18F]-penciclovir), 18F-FESP ([18F]-fluoroethylspiperone),
18F-p-MPPF
(4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-[18p]fluorobenzamido]ethylpip-
erazine) and 18F-FDG ([18F]-2-deoxy-2-fluoro-D-glucose).
[0083] "Radioactivity concentration" is an amount of any specified
radioisotope in a sample and is usually measured as Curies per
Liter, where Curie Per Liter (Ci/L) has a dimension of
L.sup.-3T.sup.-1 where L is length, and T is time.
[0084] "Kryptofix" or "K222" is a tradename for commercially
available cryptands. Cryptands are a family of synthetic bi- and
polycyclic multidentate ligands for a variety of cations. These
molecules are three dimensional analogues of crown ethers but are
more selective and complex. The most common and most important
cryptand is
N[CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.3N. This
compound is termed [2.2.2]cryptand where the numbers indicate the
number of ether oxygen atoms (and hence binding sites) in each of
the three bridges between the amine nitrogen "caps". All-amine
cryptands exhibit particularly high affinity for alkali metal
cations, which has allowed the isolation of salts of K.sup.-.
[0085] Bacterial endotoxins include, for example a concentration
that is a component of gram-negative bacterial cell walls.
Endotoxins are, for example, toxins associated with certain
bacteria. It is possible to perform a test for this parameter using
an integrated device, such as Endosafe-PTS.TM., made by Charles
River to test endotoxin content. The device uses a cartridge to
handle the QC and reference samples. There is a range of
measurement value in the unit of EU/ml.
[0086] The term "column" means a device that may be used to
separate, purify or concentrate chemical compounds. Such columns
include, but are not limited to, various types of High-Performance
Liquid Chromatography (HPLC) columns and Gas Chromatography (GC)
columns. For example, HPLC is liquid phase separation/detection
instrument. GC is gas phase separation/detection instrument. Both
HPLC and GC use columns. HPLC usually uses a packed column whereas
the GC typically uses a coated capillary column.
[0087] The term "sample" generally refers to a homogeneous or a
heterogeneous fluid. Solution is an example of a homogeneous fluid.
Heterogeneous fluid such as, for example, a suspension or slurry,
contains solid particles, for example, insoluble reagents or
products, or beads (reagents on solid support). Heterogeneous
fluids also include emulsions or colloids. Embodiments of the
present invention typically have better results with homogenous
solutions since such solutions are typically provide better
results, especially with respect to color and appearance tests.
[0088] Some examples of the radiolabeled compounds that may be
analyzed according to one or more embodiments of the present
invention include compounds selected from the group of
2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG),
6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA),
6-[18F]fluoro-L-meta-tyrosine ([18F]FMT),
9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine ([18F]FHBG),
9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG),
3-(2'-[18F]fluoroethyl)spiperone ([18F]FESP),
3'-deoxy-3-[18F]fluorothymidine ([18F]FLT),
4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl[ethyl]-N-2-pyridiny-
l-benzamide([18F]p-MPPF),
2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidine)malonon-
itrile ([18F]FDDNP), 2-[18F]fluoro-.alpha.-methyltyrosine,
[18F]fluoromisonidazole ([18F]FMISO) and
5-[18F]fluoro-2'-deoxyuridine ([18F]FdUrd).
[0089] FIG. 1 illustrates a flowchart of steps 10 according to an
embodiment of the present invention. Flowchart 10 is typically, for
example, a series of steps or program code, such as executable, or
computer code, that maybe stored on a computer-readable medium or
other electronic storage medium, such as a RAM, ROM, EEPROM, CD,
DVD, non-volatile memory, removable memory card or non-transitory
electronic storage medium. The steps 10 may be executed by a
processor, or otherwise executed or implemented to perform the
identified functions and may also be stored in one or more
electronic memories.
[0090] The method shown in FIG. 1 is used for an automated quality
control analysis of an agent, such as a PET tracer, and includes a
start step 100. The process shown in FIG. 1 is in-line because the
same sample, from a single injection, or source is used to perform
quality testing. Step 102 shows that a single injection of a sample
is loaded for complete analysis. In step 104, a measurement value
for particle and color content is determined. In step 106, a
measurement value for sterility based on a filter membrane
integrity (after the entire amount of product has been passed
through it) is determined. The filter membrane test is primarily
used to ensure its integrity after use. In step 108, a measurement
value for bacterial endotoxins concentration is determined. As
shown by line 105, the test for filter membrane integrity does not
require any sample. Also, as shown by line 107, the endotoxin
concentration test may use additional sample loading. The filter
membrane integrity test and the endotoxin concentration test are
two separate tests.
[0091] In step 110, a measurement value for radiochemical purity is
determined.
[0092] In step 112, a measurement value radiochemical identity is
determined. In step 114, a measurement value for radionuclidic
purity is determined. In step 116, a measurement value of
radioactivity concentration is determined. In step 118, a
measurement value for specific activity is determined. In step 120,
a measurement value for Kryptofix concentration is determined. In
step 122, a measurement value for residual solvent volume is
determined. In step 124, a measurement value for pH of the sample
solution is determined. In step 128, a comparison is made between
each measured value and an associated predetermined quantity to
determine whether each measured parameter is satisfactory, i.e.,
"passes". Step 128 is also reached via line 103 which shows that
the measurement of parameters can be parallel.
[0093] Indeed, each test may be performed while the other tests are
being performed. That is, all the measurements do not be performed
in a sequence. This feature of parallel determinations enhances the
speed at which the tests can be performed. Step 130 shows that each
measured parameter must pass the associated test for the sample to
pass. Specifically, "no" line 132 shows that a step of generating a
report (146) and/or providing the reason for the failure (164) as
well as end step 170 is reached if the sample does not pass each
test.
[0094] When a sample passes a particular test, "yes" line 134 leads
to step 136 which determines whether all desired test parameters
have been accounted. If there are additional parameters, "yes" line
138 leads to step 128. When all desired parameters are identified
and have deemed satisfactory, a cumulative rating for the sample is
determined in step 144 via line 140. A report is generated in step
146. This report can provide an explanation of each test performed
and the result of each test. The report may be saved, step 150,
transmitted, step 154, and/or output, step 158.
[0095] A determination whether to release the sample is made in
step 160. If so, "yes" line 166 shows that the sample is released
as shown in step 168 and end step 170 is reached.
[0096] Even though a sample passes each test, the sample may not be
released for another reason, as shown by "no" line 162 that shows a
report providing the reason for failure may be generated as shown
in step 164. The reason for such a failure, other than failing a
particular test, may be improper test conditions, inadequate sample
size or other basis. End step 170 is then reached
[0097] FIG. 2A shows a schematic of an apparatus, or QC system, 20
of a plurality of testing modules used for quality control. As
shown in FIG. 2A, system 20 is a network system in which various
testing modules are operatively coupled to one another and
processor module 242 via network 240.
[0098] The network 240 is, for example, any combination of linked
computers, or processing devices, adapted to transfer (transmit
and/or receive) and process data. The network 240 may include
wireless and wired transmission capabilities. The network 240 may
be a private Internet Protocol (IP) network, as well as a public IP
network, such as the Internet that can utilize World Wide Web (www)
browsing functionality. Alternatively the network 240 may be an
Ethernet network, or any two or more operatively coupled processing
devices that can share information.
[0099] An example of a wired network is a network that uses
communication busses and MODEMS, or DSL lines, or a local area
network (LAN) or a wide area network (WAN) to transmit and receive
data between terminals (such as processor 242 and testing or
measurement modules 204, 206, 208, 210, 211, 212 and 214). An
example of a wireless network is a wireless LAN. Global System for
Mobile Communication (GSM) is another example of a wireless
network. The GSM network is divided into three major systems which
are the switching system, the base station system, and the
operation and support system (GSM). Also, IEEE 802.11 (Wi-Fi) is a
commonly used wireless network in computer systems, which enables
connection to the Internet or other machines that have Wi-Fi
functionality. Wi-Fi networks broadcast radio waves that can be
picked up by Wi-Fi receivers that are attached to different
computers. As shown in FIG. 2A, the network 240 is coupled to
processing device 242 via wired or wireless bi-directional
communication medium 230.
[0100] The apparatus 20 may be used for inline testing for
performing a plurality of tests for quality control. For example,
particle and color content module 206 is used for determining
particle and color parameters. For example, this test compares an
identified color with a predetermined range for color
acceptability.
[0101] Filter membrane integrity module 204 is used to determine
sterility of a sample based on the speed of a pressure drop after
the membrane has been pressurized with gas (after it has been used
for filtering the product. A schematic for the filter membrane
integrity test is shown in FIG. 3.
[0102] Radiochemical module 210 is used for determination of
radiochemical identity, radiochemical purity, radioactive
concentration and specific activity. A schematic for these tests is
shown in FIGS. 5, and 12.
[0103] Radionuclidic purity module 211 is used to determine the
radionuclidic purity of a sample. A schematic for this test is
shown in FIGS. 5 and 12.
[0104] A pH of a sample solution is determined using pH module 214.
A schematic for the pH test is shown in FIG. 5.
[0105] A GC module 212 is used for determination of Kryptofix
concentration and residual solvent concentration. A schematic for
the Krytofix test is shown in FIG. 5.
[0106] A bacterial endotoxins concentration module 208 performs
endotoxins test, which are toxins associated with certain
bacteria.
[0107] Processor module 242 is used to compare control parameters,
obtained from the modules described above with predetermined
corresponding criterion values and to generate a cumulative quality
rating for the sample.
[0108] Report module 246 is used to generate a report for the
sample based on the quality rating. This report can be transmitted
to a pharmacist or a researcher to provide information for a dose
sample of a biomarker to be further used in clinic or research. The
report can be transmitted via network 240 to another destination
(not shown).
[0109] Each module described above may be coupled to one or more
processing modules. While a single processing module 242 is shown
for description purposes, additional processing modules may be used
for efficiency.
[0110] FIG. 2B shows another embodiment 25 of an apparatus
according to the present invention. FIG. 2B shows modules as part
of a processing device 242. The modules of FIG. 2B are typically
program code that include algorithms to calculate values based on
measured data, as shown in FIG. 2A.
[0111] Processor unit, or module 242 is typically a system control
unit that generates a report, performs processing and transmits the
data over network 240, displays (236), and/or prints (232) and/or
stores (234) the processed data.
[0112] Processor unit 242 typically includes a CPU 296 and memory
292 to perform the necessary data processing and storage
functions.
[0113] Processing unit, or device, or module, or terminal, 242 is
typically one or more computers, or other processing device(s),
wireless processing device, personal computer (PC), desktop,
notebook, information appliance and the like. The processing device
242 typically includes processing (296) and storage (292) modules.
The processor 242 is coupled to network 240 via bi-directional
communication medium 230.
[0114] The image display unit, or module, 236 is coupled to
processor unit 242 via bidirectional communication medium, which is
typically a bus or wired connection or wireless connection. The
display unit 236 is used to display the report or output data
generated processor module 242. The display unit 236 may be, for
example, a monitor, LCD (liquid crystal display), a plasma screen,
a graphical user interface (GUI) or other module adapted to display
output data typically by a representation of pixels.
[0115] The processing module 242 may also be coupled to a printer
232 to print the output, or a transmission module, such as a DSL
line (not shown) or a modem, such as a wireless modem (not shown),
to transmit the output to a second location or another display
module. This transmission may also be accomplished using a network
240, such as the Internet, with web browsing capability, or other
network of operatively coupled computers, processors, or output
devices. Memory module 234 is additional electronic storage device
and can be used to store data.
[0116] Memory module 292 is, for example, an electronic storage
medium, such as a server, or other electronic storage repository
that can store data. The memory module 292 may include, for
example, RAM, ROM, EEPROM or other memory media, such as an optical
disk, optical tape, CD, or a floppy disk, a hard disk, or a
removable cartridge, on which digital information is stored in the
form of bits. The memory module 292 is shown as coupled to
processing module 296 via wired or wireless bi-directional
communication medium. The memory module has program storage
294.
[0117] The CPU 296 is typically a processor that includes an
arithmetic logic unit (ALU), which performs arithmetic and logical
operations, and a control unit (CU), which extracts instructions
from memory and decodes and executes them, utilizing the ALU when
necessary.
[0118] Memory module 292 is typically an electronic storage medium
such as RAM, ROM, EEPROM or other memory device, such as an optical
disk, optical tape, CD, or a floppy disk, a hard disk, or a
removable cartridge, on which digital information is stored in the
form of bits. It may also include recorders to record to and read
from mass storage devices such as, for example, optical disks,
magnetic disks, flash semiconductor disks, and other types of
storage which may be temporary or permanent.
[0119] The memory module 292 stores programs in program module 294.
Program module 294 includes, for example, a web browser (not
shown), particle content module 252, color content module 254,
filter membrane integrity module 256, bacterial endotoxin module
270, Kryptofix concentration module 272, residual solvent volume
module 274, radiochemical identity module 258, radiochemical purity
module 266, radionuclidic purity module 260, radioactive
concentration module 264, specific activity module 262, pH module
268. Standard storage module 290, comparison module 280 and report
module 286. Each of these modules perform the associated function
described herein.
[0120] Standard storage module 290 is used to store predetermined
criteria for various parameters. Comparison module 280 makes a
comparison between each measured value and an associated
predetermined quantity to determine whether each measured parameter
is satisfactory, i.e., "passes". Report module 286 generates a
report identifying the outcome of each test and whether the sample
passed all of the tests.
[0121] The processing module 242 also includes typical operating
system programs (not shown), input/output programs (not shown), and
other programs that facilitate operation of processing device
242.
[0122] Memory module, or facility, 292 is used to store used or
generated by the CPU 296. The memory 292 may be accessed in such a
way that the contents of the memory are provided to the CPU 296.
Once the data has been accessed, typically by program code to
fetch, or retrieve, the desired data stored in memory, it may be
processed according to one or more algorithms described here.
[0123] FIG. 3 illustrates an example of a setup 30 for performing a
filter integrity test.
[0124] Typically, liquid pharmaceutical and biopharmaceutical
products are sterilized by filtration. The sterilizing filtration
process is designed to remove viable and non-viable particles from
the liquid passing through the filter. The particles removed from
the fluid either remain on the surface of the filter membrane or
are trapped within the membrane matrix. Integrity testing relies on
the measurement of gas flow through wetted membranes. Diffusion of
the test gas through the liquid filled pores in the membrane is a
function of the diffusion constant and the solubility of the test
gas in the liquid at the test temperature, the pressure
differential of the test gas across the membrane, the thickness of
the liquid layer, and the area and porosity of the membrane.
Usually, after wetting the filter material, a gas pressure is
applied to the inlet side and preferably the diffusive flow through
the wetted filter material measured. The pressure is then measured
in the outlet conduit as a function of time. It is then determined
whether the pressure measured at a preselected time exceeds a
reference pressure by a pre-determined amount. The filter is used
to sterilize a sample, for example a PET tracer. This test is to
make sure the filter membrane is still in good condition or
maintains its integrity after the filtration has been completed.
Otherwise the PET tracer is questionable. While the test may damage
the membrane, that is not critical or important at the test stage.
The significance of the test is whether at a threshold pressure the
filter is still acceptable or not.
[0125] It should be noted that the filter 318, features small
venting holes. A filter device (shown in FIG. 11) is designed to
block the venting holes at the time of the filter membrane
integrity test. Otherwise, the venting holes remain open. Upon
opening a valve, for example a 3-way valve, 312 to nitrogen source
302, the pressure from the nitrogen source 302 pushes the purified
sample solution out of the vial 308 and fills the vial 326 through
the filter 318, a process used to sterilize the tracer sample. An
aliquot of the sample can be taken out from the vial 326 for the
following QC tests with the syringe 320. The sterile sample vial
may also be equipped with an additional filter vent 322. The filter
vent 322 is disposed in valve 312, which is connected to vial 236
via conduit, such as tubing, 346. Then the 3-way valve 312 is
switched to close nitrogen source 302 and open nitrogen source 304.
A valve, for example a 2-way valve, 316 is then opened and the
pressure of nitrogen source 304 is adjusted to a desired value with
the aid of pressure gauge 314.
[0126] The 2-way valve 316 is then closed. The filter 318 is now in
a closed, pressurized environment. If the filter membrane maintains
its integrity, the pressure should be fairly constant, or drop
slowly with time. For example the pressure for acceptable membrane
integrity is typically greater than or equal to 50 psig. Otherwise
a quick drop in pressure is observed. Results of the membrane
integrity test are shown in FIG. 6.
[0127] FIG. 4 shows a schematic 40 of an automated radiochemical QC
system. The modules shown in schematic 40 are used to complete a QC
process in approximately 15 minutes thereby providing a PET tracer
a Certificate of Analysis with 11 parameters. These 11 parameters
are obtained through: 1.) pressure drop measurement; 2.)
Endosafe-PTS measurement; 3.) HPLC analysis; 4.) decay measurement;
5.) color/particle measurement; 6.) pH measurement; and 7.) GC
analysis. A computer, or processing terminal, controls the parallel
QC processes and acquires data from all measurement stages,
modules. As shown in FIG. 4, control commands are provided from
computer 440 via communication medium 435 to each module, and data
is provided from the testing modules to computer 440 via data
communication medium 437. A report is generated at report, or
certificate of analysis is provided by module 446, based on data
received from computer 440 via communication path 442.
[0128] Specifically, module 406 shows that a filter membrane
integrity test is performed. Module 408 shows that an endotoxin
test is performed. Module 412 shows that a radiochemical
identification test, radioactivity concentration test,
radiochemical purity test and specific activity test are performed.
Module 414 shows that a radionuclidic purity test is performed.
Module 415 shows that color/particulate/clarity test is performed.
Module 424 shows that a pH test is performed. Module 426 shows that
an organic solvents test and Kryptofix test is performed.
[0129] FIG. 5 shows a schematic 50 including GC unit, HPLC unit,
radioactivity detection unit for determining radionuclidic purity,
color and appearance (clarity) unit and pH unit. FIG. 5 shows
in-line HPLC related analyses for radiochemical identity;
radiochemical purity; and specific activity test. The syringe 501
delivers sample solution to fill the GC injection valve 503, the
HPLC injection valve 502 and the downstream detection/measurement
units. Since the quantity of the sample is typically between
approximately one nanolitre and approximately one microliter, the
loading of the sample to HPLC and GC may be considered
microfluidic. Furthermore, while the sample in the valve 502 and
503 is used for high performance liquid chromatography (HPLC) and
GC related analysis, the sample in a section of the downstream
tubing 508 underneath the radiation detection module 505 is used to
record the decay of the radioactivity over a period of time. The
decay recording is followed by an exponential curve fitting.
[0130] The GC unit includes a GC injection valve 503 that receives
sample from syringe 501. The GC unit is used to determine organic
solvent content and Kryptofix content analysis. Two additional
parallel analyses, GC analysis for residual solvent volume and
bacterial endotoxins concentration analysis, can be included to
complete the QC system described herein. Instruments for both of
these analyses are commercially available. While GC is capable of
analyzing the content of organic impurities in a few minutes, the
endosafe-pts from Charles River is a point-of-use test system
providing quantitative endotoxin results in about 15 minutes. The
sample sizes are from a few micro-liters for GC analysis and two 25
micro-liters for endotoxin test. A robotic system can be used for
loading the sample into these testing modules. Both of these
systems are integrated into the Auto QC instrument, thus avoiding
the need for the user to perform manual injections, which are
statistically the largest source of error during QC.
[0131] As an alternative to the GC-based test, the sample fills the
Kryptofix test unit and mixes with iodine loaded by a syringe (not
shown). The Kryptofix reacts with Iodine, generating a colored
substance which can be easily detected with a light source and a
photo-detector. A T-shape micro-channel structure (shown in FIG. 10
herein) is designed to make sure a thorough mixing and quick
detection of Kryptofix.
[0132] Alternatively, microfluidics can be used for Kryptofix test,
which is based on mixing of laminar flow of three streams of fluid
inside a small scale channel (1 mm wide, 100 .mu.m deep) created on
a 7.5 cm by 2.5 cm cast acrylic base (FIG. 10). A silicone adhesive
is attached to the top surface of the base creating the end wall
for the channel system. Two side ports are used for loading
standard and sample solution while the middle port is used for
iodine solution. As the solutions flow downstream the channel,
diffusion, mixing and reaction progress. The developed color can be
used to quantify the concentration of Kryptofix in sample as
compared with that in standard.
[0133] The GC injection valve 503 then allows the sample to enter
the HPLC unit via conduit, or tubing 511.
[0134] The HPLC unit is an analytical instrument which typically
consists of a high pressure liquid pump (not shown), a loop valve
502 (shown in the inject position), loop 560, a column (not shown),
and suitable detection units, to perform radiochemical
identification test, radioactivity concentration test,
radiochemical purity test and specific activity test. The HPLC unit
has the resolving power to separate a mixture into individual
components, making the subsequent analysis possible.
[0135] Each HPLC separation generates two traces in the
chromatogram, a UV absorbance trace and a radioactivity trace. The
retention time for the desired compound is defined as radiochemical
identity. The radioactivity of the desired PET tracer from a fixed
volume is called radioactivity concentration. On the radioactivity
trace, the ratio of peak area of the desired compound to the total
peak area of all compounds is defined as radiochemical purity. For
desired compound, such as PET tracer, the peak area in the
radioactivity trace over that in the UV trace translates into
specific activity.
[0136] The radioactivity detection unit 505 is used for determining
radionuclidic purity of the sample. The radioactivity signal from
module 505 is used to determine radionuclidic purity of the sample.
The sample reaches radioactivity detection module 505 via conduit
508. The half life, T.sub.1/2 from the exponential equation of the
fitted curve is an indication of the radionuclidic content and
purity.
[0137] Embodiments of the present invention allow both the specific
activity measurement (concentrated) and the radiochemical purity
(dilute) to be performed with a single injection of a sample (see,
for example, a representative schematic 1200 on FIG. 12). This is
achieved by changing the sensitivity of the HPLC radiation detector
based on the signal measured by the in-line radiation detector.
[0138] Color and appearance unit 580 analyzes the sample for
particle (appearance) and color content. The color test typically
uses a visible light source (not shown) and a spectrometer, for
example a CCD spectrometer (not shown), both equipped with fiber
optics. A colored test solution in the flow cell absorbs light at
certain wavelength. The absorbance spectrum can be used to
characterize the color of the sample. The CCD spectrometer is used
to measure the appearance. Details of the color test are provided
with respect to FIG. 13.
[0139] The color and appearance (clarity) tests may, alternatively,
be microfluidic since they may occur in a capillary channel.
[0140] The pH unit 570 is typically a pH cell with a micro pH
electrode, which is capable of micro-liter pH test. A valve, such
as a 6 position, 7-port distribution valve (not shown) may be used
to select solutions, including three standard pH solutions, for
example, pH 4.01, pH 7.01 and pH 10.01, and an electrode storage
solution. The three pH standards are used to routinely calibrate
the pH electrode of the pH unit 570 while the storage solution is
introduced into the pH unit 570 in case the pH electrode is not in
use.
[0141] Waste location 552 is also shown. The sample is deposited in
waste location 552 following the test procedure. Based on the
results of the test of the sample, the remainder of the sample will
either pass or fail the requirements for use.
[0142] A sample chromatogram showing UV absorbance and
radioactivity is exemplified on FIG. 7 herein.
[0143] An alternative option for the GC unit described above,
involves a miniGC or a microGC which is chip based and contains an
automated loading mechanism, eliminating the need for an injection
syringe. The miniGC or micoGC are instruments that are miniaturized
and specialized to perform a specified function. The devices are
used separate and detect organic impurities.
[0144] Once the analysis of a sample has been performed, the
results of all tests are analyzed automatically within the pre-set
limits and the dose is qualified as passing or failing in each of
the tests and overall. This information can be transferred to the
user remotely (the user does not even need to be in the lab) and
allow them to release the dose for human use.
[0145] For example, a technician can run the instrument and the
report can be submitted to a pharmacist remotely. This way one
pharmacist can validate/release doses in several locations
involving minimal staff.
[0146] Finally when the full QC run has been completed, the system
performs a self-cleaning and calibration cycle automatically, after
which it is ready for the next run.
[0147] FIG. 6 shows membrane integrity test results 60 in
accordance with an embodiment of the present invention. As shown in
FIG. 6, time in units of seconds is shown on the X-axis 602 and
pressure in units of psi are shown on the Y-axis 604. Line 606
shows a relatively slow pressure drop over time while line 608
shows a much faster relative pressure drop. When a filter membrane
keeps its integrity, the pressure will drop according to line 606
rather than 608, which is a relatively precipitous drop in
pressure. This is particularly evident within the initial 10
seconds.
[0148] FIG. 7 shows UV absorbance and radioactivity chromatograms
70 generated through HPLC separation and detection of [.sup.18F]FLT
in accordance with an embodiment of the present invention. As shown
in FIG. 7, UV absorbance chromatogram 72 shows time in seconds on
the X-axis 702 and absorbance coefficient is shown on the Y-axis
704. Line 720 shows the plot of UV absorbance. A first peak 742 is
shown followed by peak 740 indicating the presence of FLT compound
with a retention time of about 240 seconds.
[0149] Radioactivity chromatogram 74 shows time in seconds on the
X-axis 752 and radioactivity range from 0 to 1600 is shown on the
Y-axis 754. Line 760 shows a plot of the radioactivity. Peak 762
with radioactivity reading of approximately 1500 corresponds to FLT
compound.
[0150] FIG. 8 shows radionuclidic test results 80 based of decay
measurement of [.sup.18F]FLT in accordance with an embodiment of
the present invention. Time in seconds is shown on the X-axis 802
and radioactivity is shown on the Y-axis 804. Line 820 shows an
exponential fit of decay of .sup.18F FLT to the measured signal,
represented by dots 840.
[0151] FIG. 9 shows ethanol, acetonitrile and Kryptofix GC test
results 90 in accordance with an embodiment of the present
invention. Time in seconds is shown on the X-axis 902 and
ionization signal in .mu.V is shown on the Y-axis 904. (Y-axis 904
includes 904(a) and 904(b), in which 904(b) is an expanded portion
of 904(a).) Chromatogram 910 includes expanded portions 920 and
940. Expanded portion 920 includes peaks for ethanol 922 and
acetonitrile 924. Expanded portion 940 shows the peak for Kryptofix
944. The Kryptofix test described herein is an automated test that
incorporates two steps, previously performed separately, into a
single GC operation. This is shown in FIG. 9 where both organic
solvents (ethanol and acetonitrile) and Kryptofix are measured in a
single GC operation.
[0152] FIG. 10 shows a microfluidic structure 1000 used to
characterize Kryptofix content in a sample in accordance with an
embodiment of the present invention. The structure 1000 includes
substrate portion 1002 that includes three inlets 1004, 1006 and
1008 and a common waste outlet 1030. The middle inlet 1008 supplies
iodine solution while the side inlets 1004, 1006 supply both sample
solution and standard. Channel 1010 provides a conduit or fluid
path from inlets 1004, 1006 and 1008 to waste 1030. All devices are
designed such that they can be operated either manually or
automatically.
[0153] FIG. 11 illustrates a filter device 1100 where venting holes
can be blocked in accordance with an embodiment of the present
invention. The device 1100 includes a first rectangular plate 1102
and a second rectangular plate 1108. While the first plate 1102 and
second plate 1108 are shown as rectangular in shape, any suitable
shape may be used. The plate 1102 has an upper surface 1104 and a
channel 1106. Plate 1108 is mounted on circular filter member 1116,
and contains a membrane. Circular filter member 1116 is in
proximity to surface 1104. Two holes, or vias, 1120 and 1130 are
shown in plate 1108. These holes 1120, 1130 are used to tighten the
two plates 1104 and 1108 together in order to seal the venting
holes of the filter 1116.
[0154] FIG. 12 shows a schematic 1200 for test parameters according
to an embodiment of the present invention. Syringe 1201 provides a
single sample injection. The sample from syringe 1201 is provided
to GC injection valve 1203, which can also receive Nitrogen. A
compressed gas source 1209 is operatively coupled to the GC valve
1203. The sample from syringe 1201 fills the downstream modules, as
shown herein. The sample also flows to HPLC injection valve 1202,
via conduit 1211. HPLC injection valve 1202 may be in a loading
mode or an injection mode. In a loading mode, the sample does not
flow to loop 1260. In the injection mode, valve 1202 permits the
sample to flow to loop 1260.
[0155] An HPLC pump 1240 is used to pump the sample through the
HPLC column 1242. Loop 1260 and HPLC column 1242 are also shown.
Conduit 1206, which is a flow channel, such as suitable tubing,
provides sample to variable radiation sensitivity unit, or module
1212. The variable radiation sensitivity module 1212 includes a
first radioactivity detection module 1204 and a second
radioactivity detection module 1205. First radioactivity detection
module 1204 receives a portion of the sample via conduit 1206
(which has come from HPLC column 1242. Second radioactivity
detection module 1205 receives a portion of the sample via conduit
1208.
[0156] Based on the radioactivity signal from the second
radioactivity detection module 1205, the length of tubing, or
detection volume, underneath both radioactivity detection modules
1204, 1205 can be adjusted simultaneously with pneumatic actuators
(not shown). This feature allows the radiation detectors (1204,
1205) to work in the linear detection range. This sensitivity
adjustment only takes a few seconds, but it may save more than 10
minutes for an additional HPLC separation. (In manual QC, two HPLC
injections may be required--concentrate sample for the specific
activity and dilute sample for the radiochemical purity). As shown
in FIG. 12, both of these analyses may be performed with a single
sample injection from syringe 1201.
[0157] A sample portion from radioactivity detection module 1204
flows to UV detector 1228 for further testing and then to waste
location 1250.
[0158] A sample portion from radioactivity detection module 1205
flows to an optical flow cell 1280 is used to test color and
appearance. The color test uses a visible light source and a CCD
spectrometer, both equipped with fiber optics. The color test is
described in more detail above as well as with respect to FIG.
13.
[0159] The last portion of the sample fills a pH flow cell 1270,
where a micro pH electrode is capable of micro-liter pH test. The
pH test is described herein. (See FIG. 5.) The sample portion then
flows to waste location 1252.
[0160] In another embodiment, the present invention provides a
variable radiation sensitivity mechanism. In manual QC, two HPLC
injections are usually required--a concentrated sample for the
specific activity (or UV) and a dilute sample for the radiochemical
purity. The embodiments of the current invention allow both of
these analyses to be performed with a single sample injection. This
can be accomplished by adjusting the radiation sensitivity, so the
radiochemical analysis of a concentrated sample can be performed.
Based on the radioactivity signal from the module 1212, the length
of tubing, or detection volume, underneath both radioactivity
detection modules (1204, 1205) can be adjusted simultaneously with
pneumatic actuators (not shown). This feature allows the radiation
detectors always work in the linear detection range. This
sensitivity adjustment only takes a few seconds, but it may save
more than 10 minutes for an additional HPLC separation.
[0161] Traditionally, GC is used for organic solvent analysis and
iodine spot is used for Kryptofix test. The current invention
combines the two in a single GC operation.
[0162] The GC sample can be injected either with a syringe, or a
heated sample injection valve. The valve allows GC to be inline
with the rest of test operation.
[0163] FIG. 13 shows a schematic 1300 for color and appearance test
according to an embodiment of the present invention. A portion of
the test sample is introduced to optical flow cell 1350 via sample
inlet 1368. The color test uses a visible light source 1324 and a
CCD spectrometer 1328, both equipped with fiber optics 1342 and
1340, respectively. A colored sample in the optical flow cell 1350
absorbs light at certain wavelength. The absorbance spectrum can be
used to characterize the color of the sample. The CCD spectrometer
1328 may be used to measure the appearance. The light source for
appearance is from a solid-state laser 1332, which is positioned
substantially perpendicular to the detection fiber optic 1340. The
degree of light scatter reflects the particulate content, or
appearance, of the sample. Sample outlet 1370 provides an output
for the test sample from optical flow cell 1350.
[0164] FIG. 14 shows a QC system 1400 for a plurality of tests
according to the present invention. These tests include
radiochemical identification, radiochemical purity, specific
activity, pH, radionuclidic purity, radioactivity concentration,
and K222.
[0165] System 1400 includes an injection valve 1402, used to inject
sample from a single injection to loop 1460. In loop 1460,
radiochemical identification, radiochemical purity and specific
activity tests are performed.
[0166] The sample flows through conduit 1462 from loop 1460 to
distribution valve 1406. A portion of sample is provided to a
module 1410, having electrode 1408 for performing pH, radionuclidic
purity and radioactivity concentration tests.
[0167] A portion of the sample flows through valve 1464 and tubing,
or conduit, 1466 to K222 module 1474 for testing. The K222 module
1474 has an associated light source 1472 and detector 1476. Iodine
is introduced via source 1470 to 3 way valve 1412. A portion of the
sample may be drawn via syringe 1420. The portion may then flow to
waste location 1450.
[0168] FIG. 15 illustrates an example of a setup 1500 for
performing a color and appearance test and a filter integrity
test.
[0169] Typically, liquid pharmaceutical and biopharmaceutical
products are sterilized by filtration. The sterilizing filtration
process is designed to remove viable and non-viable particles from
the liquid passing through the filter. The particles removed from
the fluid either remain on the surface of the filter membrane or
are trapped within the membrane matrix. Integrity testing relies on
the measurement of gas flow through wetted membranes. Diffusion of
the test gas through the liquid filled pores in the membrane is a
function of the diffusion constant and the solubility of the test
gas in the liquid at the test temperature, the pressure
differential of the test gas across the membrane, the thickness of
the liquid layer, and the area and porosity of the membrane.
Usually, after wetting the filter material, a gas pressure is
applied to the inlet side and preferably the diffusive flow through
the wetted filter material measured. The pressure is then measured
in the outlet conduit as a function of time. It is then determined
whether the pressure measured at a preselected time exceeds a
reference pressure by a pre-determined amount. The filter is used
to sterilize a sample, for example a PET tracer. This test is to
make sure the filter membrane is still in good condition or
maintains its integrity. Otherwise the PET tracer is questionable.
While the test may damage the membrane, that is not critical or
important at the test stage. The significance of the test is
whether at a threshold pressure the filter is still acceptable or
not.
[0170] It should be noted that the filter 318, features small
venting holes. A filter device (shown in FIG. 11) is designed to
block the venting holes at the time of the filter membrane
integrity test. Otherwise, the venting holes remain open. Upon
opening a valve, for example a 3-way valve, 1512 to nitrogen source
1502, the pressure from the nitrogen source 1502 pushes the
purified sample solution out of the vial 1508 and fills the vial
1526 through the filter 1518, a process used to sterilize the
tracer sample. An aliquot of the sample can be taken out from the
vial 1526 for the following QC tests with the syringe 1520. The
sterile sample vial may also be equipped with an additional filter
vent 1522, which is connected to vial 1526 via conduit, such as
tubing, 1546. Then the 3-way valve 1512 is switched to close
nitrogen source 1502 and open nitrogen source 1504. A valve, for
example a 2-way valve, 1516 is then opened and the pressure of
nitrogen source 1504 is adjusted to a desired value with the aid of
pressure gauge 1514.
[0171] The 2-way valve 1516 is then closed. The filter 1518 is now
in a closed, pressurized environment. If the filter membrane
maintains its integrity, the pressure should be fairly constant, or
drop slowly with time. For example the pressure for acceptable
membrane integrity is typically greater than or equal to 50 psig.
Otherwise a quick drop in pressure is observed. Results of the
membrane integrity test are shown in FIG. 6.
[0172] In addition to the membrane integrity test as described
above, the sample in vial 1526 can be analyzed for particle
(appearance) and color content. Color test uses a visible light
source 1524 and a spectrometer 1528, shown as, for example a CCD
spectrometer, both equipped with fiber optics, 1542 and 1540,
respectively. A colored test solution in the flow cell absorbs
light at certain wavelength. The absorbance spectrum can be used to
characterize the color of the sample. The CCD spectrometer 1528 is
used to measure the appearance.
[0173] The light source 1530 for appearance is from a solid-state
laser, which is positioned perpendicular to the detection fiber
optic. The degree of light scatter reflects the particulate
content, or appearance, of the sample. The vial 1526 is of suitable
optical quality, allowing optical absorbance and laser scatter to
be adequately performed. In one embodiment, one fiber optic 1542
conducts the light from the light source 1524 to the vial 1526 and
on an opposite side of the vial 1526 another fiber optic 1540
conducts the absorbed light to the spectrometer 1528. The degree of
absorbance for a colored sample is wavelength dependent. In
general, a colored sample absorbs light at one wavelength but not
at the other.
[0174] The difference or the ratio in absorbance in the two
wavelength regions determines the sample's color content. To
determine the particle content, the light source 1524 can be
blocked and the laser 1530 can be turned. The laser 1530 is
located, for example approximately 90 degrees (perpendicular) to
the fiber optic 1540 that is connected to the spectrometer 1528.
The existence of particles scatters the laser light, which is
detected with the spectrometer 1528. The intensity of the scattered
light is related to the particle content, or appearance, of the
sample.
[0175] FIG. 16 shows a schematic 1600 for radionuclidic identity
test, radioactivity concentration test, pH test and Kryptofix test.
As shown in FIG. 16, syringe 1620 is used to deliver a sample for
testing. A loop valve 1602 is operatively connected to syringe 1620
and sample loop 1660. As shown in FIG. 16, the loop valve 1602 is
in a load position for loading the sample.
[0176] The syringe 1620 is used to deliver a few microliters of the
sample solution to a GC for solvent analysis and for endotoxins
test.
[0177] The syringe 1620 delivers sample solution to fill the sample
loop 4160 and the downstream detection/measurement units. While the
sample in the loop 1660 is used for high performance liquid
chromatography (HPLC) related analysis, the sample in a section of
the downstream tubing 1662 underneath the radiation detection
module 1604 is used to record the decay of the radioactivity over a
period of time. The decay recording is followed by an exponential
curve fitting.
[0178] The half life, T.sub.1/2, from the exponential equation of
the fitted curve is an indication of the radionuclidic purity. The
same module 1604 is used to determine the sample's radioactivity
concentration, which is defined as the radioactivity per unit of
solution volume. A distribution valve 1606 follows radioactivity
detection module 1604.
[0179] Downstream from the distribution valve 1606, via tubing
1664, is a pH cell 1610 with a micro pH electrode 1608, which is
capable of micro-liter pH test. The 6 position, 7-port distribution
valve 1606 is used to select solutions, including three standard pH
solutions, for example, pH 4.01, pH 7.01 and pH 10.01, and an
electrode storage solution. The three pH standards are used to
routinely calibrate the pH electrode 1608 while the storage
solution is introduced into the pH cell 1610 in case the pH
electrode 1608 is not in use.
[0180] The last portion of the sample fills the Kryptofix test unit
1614, and mixes with iodine loaded by the syringe 1624. The
Kryptofix reacts with Iodine, generating a colored substance which
can be easily detected with a light source 1624 and a
photo-detector 1612, both (1624, 1612) equipped with fiber optics
1642 and 1644, respectively. A T-shape micro-channel structure
(shown in FIG. 10 herein) is designed to make sure a thorough
mixing and quick detection of Kryptofix and iodine.
[0181] FIG. 17 shows a perspective view of an automated QC
apparatus 1700. As shown in FIG. 17, apparatus 1700 includes a
light source 1703 for the HPLC. A light source 1705 is used for
testing color of the sample. HPLC pump 1707 and a radiation
detectors 1709 and 1711 are shown. The radiation detector 1709 is
used in conjunction with HPLC testing and radiation detector 1711
is used to detect radioactive decay of the sample. Radiation
detector amplifiers 1713 and 1715 are also shown.
[0182] The apparatus 1700 also includes CCD light detectors 1719
and 1721 to detect light for testing as described herein. A pH
testing module 1723 and endotoxin station 1725 are also shown.
[0183] Introduction station 1727 is used to introduce sample to
apparatus 1700. The introduction station 1727 may be, for example
an injection station so that sample may be injected using a
syringe, alternatively the introduction station may be a fluid port
that enables a sample from a vial or synthesis module to be
provided to apparatus 1700. The apparatus may also include other
fluid, electrical and/or mechanical ports to permit fluid,
electrical and/or mechanical coupling of the apparatus 1700 to
additional modules and/or devices. Thus, the apparatus 1700 may be
operatively coupled to other modules to permit additional functions
and testing.
[0184] A sample handling robot 1729 and rotary valves 1731 and 1733
are also shown.
[0185] The apparatus 1700 is, for example a self-contained portable
unit and may be moved or transported. As stated above, the unit
1700 may have one or more communication ports, such as USB, or
other connectors that permit the apparatus 1700 to be fluidically,
mechanically and/or electronically connected to other modules,
apparatus, or devices. For example the apparatus 1700 may be
fluidically coupled to a synthesis module (not shown) used to
originate a sample. Alternatively, the apparatus may be coupled to
a network to permit remote analysis of a sample and provide the
test results to be transmitted to another location or destination.
The apparatus 1700 may also receive samples from a vial, cartridge,
tube or other suitable container, such as a transport vial, rather
than a syringe. The vial, cartridge, tube or container may be
radiation shielded to prevent exposure to radioactive material in
the vial. This enables a technician, or operator, to transport or
move or manipulate the sample, particularly between a synthesis
module and the testing apparatus.
[0186] The embodiments illustrated herein are representative of
in-line testing for all or any combination of the tests
described.
[0187] After the above sample tests, the results are analyzed
automatically to determine the dose quality--pass or fail based on
pre-defined criteria. This information can be transferred to the
user remotely (the user does not even need to be in the lab) and
allow them to release the dose for human use.
TABLE-US-00001 Item Parameter Range Method Sterility Membrane
filter .gtoreq.50 psig Pressure drop rate integrity Radiochemical
identity Retention time Conforms or not HPLC Radiochemical purity
Area ratio - FLT and .gtoreq.95% HPLC impurities Specific activity
Area ratio - .gtoreq.0.40 Ci/mmol HPLC Counts/Abs. Organic solvents
(ethanol, acetonitrile) 4.0-8.8%; .ltoreq.0.04% GC Volume %
Appearance Color and clarity Exceed threshold? CCD/laser scattering
Radionuclidic purity T.sub.1/2 105-115 min Decay monitoring
Radioactivity Counts/volume 1-75 mCi/ml Scintillation concentration
pH pH 5.5-8.0 Electrode K222 Concentration .ltoreq.50 .mu.g/ml
Indicator reaction Endotoxins Concentration .ltoreq.175 EU/dose
Endosafe
[0188] As an example, it has been demonstrated that an automated
quality control run of a 18F-FLT radiotracer sample was complete in
about 15 minutes. The issued report contained the following
data:
TABLE-US-00002 Test Specification Lot Results Appearance Color and
clarity: <10X Color 2.43X standard standard deviation of
reference deviation Membrane filter 50 psi pressure drops to 0.5
5.6 minutes Integrity test its value in >3 minutes Radiochemical
identity Identity: HPLC retention time Conforms within +/-5% of
standard Radiochemical Purity .gtoreq.95% 100% Specific Activity
.gtoreq.0.40 Ci/.mu.mol 6.50 Ci/.mu.mol Radionuclidic Purity
T.sub.1/2: 105-115 min 109.9 min Residual solvents Ethanol: 4.0-8.8
weight % 6.63% Acetonitrile: .ltoreq.0.04% 0% Radioactivity
Concentration 1-75 mCi/mL at EOS 28.4 mCi/mL pH 5.5-8.0 6.0 K222
.ltoreq.50 .mu.g/mL 20 .mu.g/mL Endotoxins .ltoreq.175 EU/dose 100
EU/dose
[0189] In addition, the methods and devices in accordance with the
various embodiments of the present invention may provide the
following additional features and benefits:
[0190] These and other features of the apparatus allow the quality
control of a large range of radiolabeled compounds using a
microfluidic technology.
[0191] In an embodiment, a standard for appearance test, or clarity
test is established as a function of particles per unit of volume,
or an amount of particles per unit volume. While conventional
testing for clarity was subjective, the present invention permits a
standard threshold for a compound to be a certain amount of
particles per unit volume. If the sample haws fewer particles per
unit volume than the standard, the sample passes the clarity test.
If the sample has more particles per unit volume than the standard,
the sample fails the clarity test. The standard may be set by
filtering a clear sample that will not exhibit any scattering. A
minimum scattering may then be set for a compound.
[0192] In another embodiment, the measurement value of sterility as
a function of membrane filter integrity, is a 50 psi drop too
one-half its value in 5.6 minutes, which exceeds the 3 minute
threshold.
[0193] In another embodiment, the measurement value of
radiochemical purity, retention time is conforming, as seen by the
result of 100 percent.
[0194] In another embodiment, the measurement value of
radiochemical purity is no less than about 95%.
[0195] In another embodiment, the measurement value of specific
activity, is no less than about 0.40 Ci/.mu.mol.
[0196] In another embodiment, the measurement value of residual
organic solvents concentration is no more than 0.04% v/v.
[0197] In another embodiment, the measurement value of color
content and clarity or particle content is below the limit
specified for each individual compound.
[0198] In another embodiment, the measurement value of
radionuclidic purity for F-18, T.sub.1/2, is about 105 to 115
min.
[0199] In another embodiment, the measurement value of
radioactivity concentration is about 1 to about 75 mCi/mL.
[0200] In another embodiment, the measurement value of pH is in the
range of about 5.5 to about 8.0.
[0201] In another embodiment, the measurement value of Kryptofix
concentration does not exceed 50 .mu.g/mL.
[0202] In another embodiment, the measurement value of endotoxins
concentration does not exceed 175 EU/dose.
[0203] Generally, embodiments of the present invention are directed
to methods and apparatus (system) for an automated quality control
analysis of radiolabeled compounds, such as PET tracers, and to
improve quality and efficiency of such operation.
[0204] In another embodiment, the invention provides a plurality of
inline modules or testing devices configured to generate data about
the analyzed substance. The inline structure of such system can be
used to carry out a plurality of parallel tests on the same sample,
which can be loaded into the sample line (tubing configured to
deliver the same sample to various testing modules of the QC system
at the same time). The sample line is being filled by a single
sample injection.
[0205] In another embodiment, the present invention provides a GC
test for both, residual volume of organic solvents and Kryptofix
concentration. Traditionally, GC is used for organic solvent
analysis and iodine spot is used for Kryptofix test. Current
automated operation can encompass the two previously separate steps
into a single GC operation.
[0206] It is an embodiment of the present invention that additional
tests can be added as required by various compounds. Furthermore,
not all tests are required for each compound. Indeed, not every
compound will require each test described herein, yet may require
other tests.
[0207] The foregoing description of embodiments has been presented
for purposes of illustration and description. The foregoing
description is not intended to be exhaustive or to limit
embodiments of the present invention to the precise form disclosed,
and modifications and variations are possible in light of the above
teachings or may be acquired from practice of various
embodiments.
[0208] The embodiments discussed herein were chosen and described
in order to explain the principles and the nature of various
embodiments and its practical application to enable one skilled in
the art to utilize the present invention in various embodiments and
with various modifications as are suited to the particular use
contemplated. The features of the embodiments described herein may
be combined in all possible combinations of methods, apparatus,
modules, systems and computer program products.
[0209] Having thus described in detail preferred embodiments of the
present invention, it is to be understood that the invention
defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
* * * * *